Previous studies have demonstrated the overwhelming importance of class II matching in determining the fate of vascular allografts in partially inbred miniature swine. When class II loci were genotypically matched, kidneys transplanted between animals differing for class I plus minor antigens were frequently found to induce specific tolerance in otherwise unmanipulated recipients. The major goal of this proposal is to determine the mechanisms by which this tolerance is induced and maintained. Available data indicate that limitation of T-cell help and route of antigen presentation are important factors in these mechanisms. The specific aims of this proposal are therefore to: (1) examine the immune response of tolerant animals to subsequent skin grafts bearing defined combinations of class I and/or class II differences; (2) determine the effect of further help limitation by administration of cyclosporine A (CsA) during the primary response to selectively mismatched kidney transplants; and (3) study in vitro the activities of graft infiltrating lymphocytes (GILS) isolated from tolerant kidneys.